Deep brain stimulation as a functional scalpel

# Springer-Verlag 2006 Printed in Austria

Deep brain stimulation as a functional scalpel

G. Broggi

, A. Franzini

, G. Tringali

, P. Ferroli

, C. Marras

, L. Romito

, and E. Maccagnano

1

Department of Neurosurgery, Istituto Nazionale Neurologico C. Besta, Milano, Italy

2

Department of Neurology, Istituto Nazionale Neurologico C. Besta, Milano, Italy

3

Department of Neuroradiology, Istituto Nazionale Neurologico C. Besta, Milano, Italy

Summary

Since 1995, at the Istituto Nazionale Neurologico ‘‘Carlo Besta’’ in Milan (INNCB,) 401 deep brain electrodes were implanted to treat several drug-resistant neurological syndromes (Fig. 1). More than 200 patients are still available for follow-up and therapeutical considera- tions. In this paper our experience is reviewed and pioneered fields are highlighted.

The reported series of patients extends the use of deep brain stimula- tion beyond the field of Parkinson’s disease to new fields such as cluster headache, disruptive behaviour, SUNCt, epilepsy and tardive dystonia.

The low complication rate, the reversibility of the procedure and the available image guided surgery tools will further increase the therapeutic applications of DBS. New therapeutical applications are expected for this functional scalpel.

Keywords: Deep brain stimulation; movement disorder; chronic pain; dystonia; Parkinson’s disease.

Introduction

At the beginning of the century stereotactic neurosur- gery was used on animals for experimental purpose with the aim of mapping the brain’s electrical activity and functional responses. The mapping process was fol- lowed by the development of surgery that was capable of changing function of brain, through small lesions in a ‘‘key’’ area. In the nineties, deep brain stimulation (DBS), after its optimization by Benabid [2–5], for the control of parkinsonian tremor gained worldwide the role of a promising therapeutical tool. The administra- tion of high frequency and low amplitude electric sti- mulation, allows the modulation of neuronal activity in a reversible way: the parameter of stimulation can be adapted according to the clinical response. Neverthe- less the way DBS works is still unclear. More experi- mental data are required to understand whether the interaction with the neurological functions is obtained

through the inhibition or the activation of cellular activ- ity which modulates the output of specific neural net- works. There is interest, moreover, to investigate new targets in order to find new therapeutical applications to approach otherwise untreatable diseases. The devel- opment of computer-based workstations allows the use of multimodality image sets for the surgical planning, while neuroimaging provides a functional scalpel and a powerful research tool in the hand of the neurosurgeon.

Since 1995 at Istituto Nazionale Neurologico ‘‘Carlo Besta’’ in Milan (INNCB), 401 deep brain electrodes were implanted to treat several drug-resistant neurologi- cal syndromes (Fig. 1). More than 200 patients are still available for follow-up and therapeutical considerations.

In this paper our experience is reviewed and pioneered fields are highlighted.

Patients and methods

Movement disorders

Parkinson’s disease: The long term results of 85 parkinsonian patients submitted to bilateral stereotactically guided implant of electrodes into the subthalamic nucleus (STN) are available. Mean age 55.7  7.7 yrs, duration of the disease 11.9  4.2 yrs, follow-up 25.4  16.7 yrs. UPDRS motor score were of 55.1  14.8 in off-drug and 19.0  11.0 in on-drug.

The present series extends to the long-term observation (FU>12 months) of our previous follow-up [6, 7]. Eight more patients affected by dopa-related diskinesias underwent Gpi neurostimulation.

Tremor: twelve patients underwent Voa-Vop-Zi high frequency stimu- lation (HFS). Four patients were affected by multiple sclerosis (MS), three patients by posttraumatic tremor, and five patients Parkinsonian tremor. Four patients affected by essential familial tremor, underwent Vim (HFS).

Dystonia: twenty-eight dystonic patients underwent Gpi HFS. This

series include patients affected by primary dystonia DYT 1 , DYT 1þ

(only one patient) and symptomatic dystonia (including three cases of

drug induced tardive dystonia). Onset of symptoms ranged between

2 and 50 years of age. Duration of the disease at the time of surgery ranged between 4 and 30 years. Preoperative and postoperative evalua- tion included video recording and assessment of dystonia with Burke- Fahn-Marsden Dystonia Rating Scales (BMFDRS).

Chronic pain

Posterior medial hypothalamic stimulation has been performed in 16 patients with chronic Cluster Headache (CH), one patient with short- lasting unilateral neuralgiform headache attacks with conjunctival injec- tion and tearing (SUNCT), and three patients with neurogenic facial pain.

Disruptive behaviour

Posterior medial hypothalamic stimulation has been performed in two patients with major psychorganic diseases and disruptive behaviors, all patients were institutionalized and required continuous sedation.

Epilepsy

Chronic stimulation of the posteromedial portion of the substantia nigra has been performed in one young female (age 26) suffering from

disabling posttraumatic drug resistant partial motor seizures (more than 100 seizures per month).

Surgical technique

Today different imaging modalities are available to calculate the target position coordinates by direct visu- alization of anatomical structures and by indirect cal- culations based on the commissural reference system.

Even if the approach to planned target is more accurate than several years ago, many factors may lead to an error in the final position of the electrode (e.g. MRI distortion and individual variability). So microrecording of neuro- nal activity and micro-macrostimulation is still helpful.

The introduction of this peroperative neurophysiological investigation has improved the safety and accuracy of functional neurosurgical procedures.

The day before surgery we perform accurate plan- ning by imaging. MRI (T1 and fast spin echo inversion recovery sequences with double dose of contrast-agent) is used to obtain high definition anatomical images of the intercommissural plane, allowing the calcula- tion of the midcommissural point coordinates. MR images are merged with computed tomography (CT) images obtained stereotactically (CRW or Leksell frame) through a dedicated workstation (Stealth Station Treon SofamorDanek, Medtronic Inc. Minneapolis =US). The stereotactic coordinates of the chosen target are obtained within the virtually built 3D space enriched by vessels enhancement. The planning of the target is refined com- paring the results obtained by the workstation with a dedicated software developed at our Institute (Virtu- alventriculography, Solaris), which is a self learning atlas based on the statistical analysis of previous im- plants. In this way the targeting procedures may take advantages from a probabilistic functional stereotactic atlas (Fig. 3).

Fig. 2. Target coordinates registered to the AC-PC midpoint: (a) Dystonia; (b) Parkinson’s disease; (c) tremor; (d) epilepsy; (e) cluster headache and aggressive behaviour

Fig. 1. Graphic representation of the whole series of deep brain elec-

trodes implanted since 1995 at the neurological institute ‘‘C. Besta’’,

Milan (stn subthalamic nucleus, GPi globus pallio pars interna, Vim

ventralis intermediate nucleus, Voa-Vop-Zi ventral oralis ventral poster-

ior and zona incerta, P. Hyp posterior hypothalamus, PVG periventri-

cular grey)

Most of the procedures have been performed through a 7 mm precoronaric paramedian burr hole. Microre- cording is used for the neurophysiological confirmation of the target in Parkinson’s disease. Micro and =or mac- rostimulation has been performed in all procedures to rule out the adverse effects induced by electrical current delivered at therapeutical levels.

All the procedures were conducted in local anaesthe- sia except for generalized dystonia where general anaes- thesia without curarization was preferred. Patients in general anaesthesia underwent only macrostimulation

to establish the motor threshold avoiding implants too close to the internal capsule.

The individual variability of the target along the ante- roposterior axis due to the high individual variability of the midbrain angle is considered and corrected in all the procedures below the commissural plane. In these cases a third point 8 mm below the commissural plane is considered to correct the AC-PC registered system. To verify the position of the electrode, CT was always per- formed after stereotactic surgery but before the pulse

Fig. 4. Postoperative MRI merged with the preoperative MRI planning showing electrode position (T1 weighted images)

Fig. 3. Snapshot of the virtual ventriculography program (Wandor software, Dolgo, PC, Italy) showing the plate 6 mm below the commissural plane. The trajectories to the GPi (red) and STN (black) nuclei are represented on the ventricles AP and lateral profile. Targets are represented on the corresponding axial section (green: GPi, yellow: optic tract, cyan: STN, dark dotted grey: substantia nigra, pale grey: internal capsula, pink red nucleus, dotted violet: sensory lemniscal fibres)

Fig. 5. Graphic representation of the complications (red: hemorrhage;

violet: permanent neurological deficits, yellow: transient neurological deficits, cyan: postoperative seizures, brown: hardware removal, grey:

hardware failure, black: electrodes migration, green: no complications)

generator was placed. This examem is merged with the preoperative planning in order to verify the electrode position [11] (Fig. 4).

Results

Movement disorders

Parkinson’s disease: At a follow-up of 25.4  16.7 months UPDRS in off-drug with stimulation is 26.4  11.7, while in on-drug with stimulation is 15.4  9.1.

The variation off =offþ stimulation is 52.1% and vari- ation on =on þ stimulation is 19.1%.

Dystonia: All patients showed a clinical improvement, as evaluated by the BMFDRS scales, that ranged be- tween 27 and 88%. The improvement was progressive over a period of 3–6 months after surgery, and persisted during the follow-up (4–48 months). Our results demon- strate that DBS is an effective treatment for dystonia, with no remarkable side effects, even in childhood. In tardive dystonia the results are higher than 90% with immediate effects.

Tremor: All patients regained autonomous self feed- ing and personal care at 12–36 months follow-up with continuous high frequency stimulation. All Vim, Voa- Vop-Zi targets showed efficacious results but the latter allowed a better control of the ataxic component.

Chronic pain

Cluster headache: At four years follow-up the percen- tage of the total number of days free from pain attacks improved from up to 78% and 10 patients of this series had a complete and persistent pain-free state.

SUNCT: At 18 months follow-up the patient had com- plete pain relief.

Neurogenic facial pain: Neurostimulation procedure was absolutely unsuccessful.

Disruptive behaviour

Stable improvement with a 12 months follow-up was obtained and a marked reduction in sedative drugs was achieved allowing us to stop the contentive hospital procedures.

Epilepsy

At 15 months follow-up the only operated patient re- ported a 60% dramatic reduction of seizures.

Complications

Massive brain haemorrhage occurred in one case of STN implant (0.4%); permanent neurological deficits due to deep haemorrhage occurred in four patients of which one was a Vim implant and the other STN im- plants (1%). Transient neurological deficits due to deep haemorrhage occurred in five patients (1.2%); post- operative seizures occurred in three patients (0.7%);

hardware removal due to infection occurred in twenty- two cases (5.4%) one of which had cerebral abscess at the origin of the stereotactic trajectory; hardware failure occurred in twelve patients (2.9%); late electrode migra- tion occurred in twelve patients (2.9%) of which eight were under fourteen years old.

Risk rate is referred to single electrode implant sur- gery, patients who need more than one electrode implant may expect a higher risk rate.

Discussion

Movement disorders

Parkinson’s disease: As far as the field of movement disorders is concerned, advanced Parkinson’s disease remains the main indication for DBS. Drug treatment of parkinsonian symptoms unfortunately cannot avoid disability in an advanced course of disease since long- term levodopa therapy often results in invalidating motor fluctuations and dyskinesias. In the 1980s, the side effects and limits of chronic L-dopa therapy became obvious and led to reintroduction of the surgical treat- ment of motor symptoms in Parkinson’s disease (PD).

Advances in stereotactic surgery, neuroimaging [15,

16], electrophysiologic recordings and the possibility

to obtain therapeutic responses by high-frequency deep

brain stimulation (DBS) have renewed interest in the

surgical treatment of PD. During the last 10 years,

several groups have demonstrated that chronic DBS of

the VIM, subthalamic nucleus (STN), or globus pallidus

internus is an effective treatment for disabling pharma-

cotherapy-resistant motor symptoms (tremor, rigidity,

bradykinesia) in PD. Increasingly evidence in favour

of the subthalamic nucleus (STN) as the target of choice

has been collected [4–6]. The experimental data in

MPTP monkeys along with clinical results in human

PD patients after both STN lesion or high frequency

stimulation, point toward a major role of STN hyperac-

tivity in the pathophysiology of PD. Deep brain stimula-

tion seems to produce a functional inhibition of the

neurons in the targeted structure that mimics the result

of lesioning. The main advantage of this procedure ver- sus lesioning is related to the reversibility and adjustabil- ity of its effects without any cerebral permanent damage.

The parameters of stimulation can be changed to in- crease efficacy or to reduce side effects. In the future a more oriented choice between the available targets (Vim- Zi-STN-Gpi-CM) will further improve clinical outcome.

Dystonia: Dystonia is a neurological syndrome charac- terized by abnormal postures and involuntary movements.

The physiopathologic basis of dystonia has not yet been completely clarified, however, the cortical-subcor- tical network and the globus pallidus internus (Gpi) are the structures primarily involved. Pharmacological treat- ment of dystonia is sometimes disappointing.

The practice of lesioning in dystonic patients was very common in the 1950s and 1960s, since at that time it was essentially the only available treatment for severe cases. These procedures, performed 50 years ago, were reported to have results not always satisfying, sometimes with severe side effects. By the 1980s, brain surgery for dystonia was abandoned. However, the increased under- standing of the pathophysiology of movement disorders and the availability of DBS technology led to a resur- gence of interest in the surgical treatment of dystonia;

with globus pallidus internus (GPi) still the favourite target [9, 13, 21]. The timing of clinical improvement observed in dystonia is different from that observed in Parkinson’s disease. In fact, days, weeks and most often months are required and, moreover, the improvement continues for years, suggesting a phenomenon of neuro- nal plasticity rather than a simple transitory functional inhibition of a pool of neurons.

Tardive dystonia (TDt) affects about 15% of patients treated by long term neuroleptics therapy and has the potential of becoming irreversible and untreatable in 1–4% of these patients. According to results from litera- ture, when drug therapy is ineffective, thalamotomy can be applied with good but sometimes transient results. Side effects such as dysarthria, dysphonia, and motor distur- bances have been described, particularly when thala- motomy is bilateral. The three patients we selected for surgical treatment presented with the typical features of drug resistant TDt: they were young males, TDt onset was observed after a long period of neuroleptics treatment, dystonia persisted after withdrawal of the causative drug with resistance to any medical treatment. Tottemberg [20]

was the first surgeon to use DBS for TDt: he investigated the effect of two different targets, VIM and GPi, on the same patient. While VIM did not result in any improve- ment of movement control, GPi did. Therefore, we treated

our patients with bilateral GPi high frequency stimula- tion. Stimulation started the first day after surgery and immediate improvement could be obtained, differently from what can be generally observed in dystonia of dif- ferent origin. In our TDt patients neuroleptic drug admin- istration was not discontinued: GPi neurostimulation was found to act as a sort of protection against this particular drug related side effect. High frequency chronic GPi stimulation was found to be safe, highly and promptly effective in these patients, and GPi stimulation has the potential to become the elective treatment of TDt, how- ever these results has to be validated by larger series.

Tremor: The impressive reduction of tremor obtained either immediately during the surgical procedure or at long term follow-up in Parkinson’s disease, lead to pro- pose neurostimulation as a suitable treatment of symp- tomatic tremor in multiple sclerosis patients. The first reported cases of midbrain electrical stimulation on mul- tiple sclerosis patients (MS) with ataxic tremor were reported by Brice and Mc Lellan in 1980. The four patients of our preliminary series were selected on the basis of major impairment provoked by intentional and at rest upper limb tremor. These findings raise the pos- sibility that ataxic tremor could benefit from chronic high frequency Voa-Vop-Zi electrical stimulation.

Pain

Pain represents one of the most challenging issues for neurosurgeons. DBS and other neuromodulation proce- dures may offer a valid alternative to ablative procedures, which always produce a permanent damage that some- times can give rise to neuropathic pain. Cluster headache (CH) in particular has been the first indication in the field of chronic pain: it was recognized starting from metabolic and functional neuroimaging which pointed to the postero medial hypothalamus. CH is a painful syndrome of the face often characterized also by symptoms of more general hypothalamic involvement such as psychomotor agitation. Recent imaging studies (PET and fMRI) dem- onstrated hypothalamic asymmetry and activation during pain attacks [13, 14, 19]. In line with these studies, sug- gesting the hypothalamus as the origin of pain attacks, we tried to interfere with the supposed hypothalamic hyper- activity through DBS.

Disruptive behaviour

Aggressive behaviour may be associated with differ-

ent psychotic diseases and =or severe oligophrenic con-

ditions. Control of aggressiveness in most cases may be obtained by drugs including phenothiazines and neuro- leptics. Nevertheless, in selected cases, control of ag- gressive behaviour may be problematic due to the need of high dosages of drugs producing major side effects and sedation, which made caring for these patients even more distressing. In the sixties several neurosurgical procedures have been proposed and performed to treat the aggressiveness in psychotic patients, but the danger of irreversible lesions to CNS structures involved in the control of cognitive functions and mood put such sur- gery in conflict with ethics. Also, electroconvulsive ther- apy (ECT) was progressively decried in the seventies due to evidence of irreversible brain damage inflicted by repeated procedures. On the other hand, the last three decades have provided a huge amount of data and knowledge about the neurophysiological mechanisms of aggressive behaviour since the first experience of Delgado on animals with neurostimulators implanted in the limbic system. Since the last decade the Delgado experience and similar experimental studies have in- spired more science fiction writers than neurosurgeons.

Bilateral stereotactic lesion of the posteromedial hy- pothalamus was first reported by Sano in the sixties.

This kind of surgery, also known as sedative neurosur- gery, found little diffusion for fear of irreversible effects.

Our recent experience of chronic hypothalamic stimula- tion for the treatment of intractable cluster headache demonstrated the feasibility and safety of this procedure and renewed our interest in this target. Deep brain sti- mulation (DBS) of the posterior hypothalamus was then performed in two patients [13]. DBS of the posterior hypothalamus could lead to a resurgence of interest in the treatment of severe behavioural disorders.

Epilepsy

Although surgical resection of the seizure focus is the treatment of choice of refractory epilepsy, DBS may be an alternative procedure when the focus involves eloquent, unresectable areas. Stimulation of different brain struc- tures such as the cerebellum (Cooper et al. 1973), the locus coeruleus (Faber and Vladyka, 1983), the thalamic centro- median nucleus (Velasco et al. 2000) and the STN-SN (Benabid et al.) has been effective in reducing seizure rate in humans [1, 9, 11, 17]. Several experimental data strongly suggested that basal ganglia and striatal pathways are involved in epileptic seizures threshold and diffusion.

Our results obtained in a young patient (26 yrs) sub- mitted to DBS procedure of the SN-pars posteromedialis.

Confirm the literature data and support application of DBS for the treatment of rolandic post-traumatic seizures.

Conclusions

The reported series of patients extend the use of DBS beyond the field of PD to new fields such as cluster headache, distruptive behaviour, SUNCT, epilepsy and tardive dystonia.

The low complication rate, the reversibility of the procedure and the available image guided surgery tools will further increase the therapeutic applications of DBS. New therapeutical applications are expected for this functional scalpel.

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Correspondence: Giovanni Broggi, Istituto Nazionale Neurologico

‘C. Besta’, Department of Neurosurgery, Via Celoria 11, 20133 Milan,

Italy. e-mail: [email protected]